Anorexia Nervosa (AN) is a major mental illness associated with substantial morbidity and mortality. Although there is agreement in the field that weight restoration is a treatment priority, no particular therapeutic approach for patients with AN has clear empirical support. The NIMH has identified AN as an illness in need of treatment research initiatives. Preliminary investigations conducted in the context of inpatient or day hospital treatment have documented that olanzapine, a second generation antipsychotic agent, has promise in the treatment of AN, leading to improvements in body weight and associated AN psychopathology. We recently completed an NIMH-supported 8-week placebo-controlled pilot study of olanzapine in the outpatient treatment of AN. Our results documented that olanzapine treatment was associated with weight gain, improvements in psychological status, and no untoward metabolic effects in low-weight patients. Thus in the present application, we propose to conduct a definitive multi-site randomized double-blind placebo-controlled trial of olanzapine versus placebo in outpatient adults with AN. In this project, 160 adults with AN will be randomly assigned to receive olanzapine or placebo for a total of 16 weeks at one of five clinical sites - Columbia University, Weill Cornell Medical College, Johns Hopkins Medical Institution, University of Pittsburgh and University of Toronto - all well known for the study and treatment of eating disorders. The study will determine whether olanzapine is more beneficial than placebo at achieving weight restoration and other measures of psychological improvement in the study participants. All study participants will receive regular Med-Plus treatment sessions that will include medical management, compliance enhancement strategies and supportive care throughout the medication trial. Clinical management will include following cardiac status and markers of metabolic syndrome to assure that any weight gain associated with olanzapine in this population is not causing untoward clinical effects. There is a critical need to identify efficacious treatments for anorexia nervosa, a pernicious disorder that is associated with significant morbidity and mortality, and for which there are no evidence-supported interventions. If olanzapine is useful in promoting weight gain and psychological recovery in adults treated in an outpatient setting, the work proposed in the application will have immediate clinical utility and significant public health impact. PUBLIC HEALTH RELEVANCE: There is no empirically supported treatment for patients with Anorexia Nervosa (AN) and rigorous study of new treatments is sorely needed. Recently published reports have suggested possible utility for olanzapine in this population, and pilot data from an NIMH-supported treatment development project suggest that olanzapine may indeed be acceptable, tolerable and offer benefit to patients with AN. This study aims to measure the potential benefit of the atypical antipsychotic medication olanzapine in a large sample of adult outpatients with AN across five clinical sites - Columbia University, Weill Cornell Medical College, Johns Hopkins, University of Pittsburgh and University of Toronto.